Under the guidance of Dr Ann Dixon and Prof. David Roper, I have studied the ligand-binding characteristics of an integral membrane protein associated with antibiotic resistance in pathogenic bacteria. Throughout the project, I built on the skills I developed during my time as a MOAC MSc student. Prior to joining MOAC, I studied Biochemistry at Aberystwyth University, and graduated with First Class Honours in the summer of 2012.

 

Academic Background

2013-2017	PhD	University of Warwick
2012-2013	MSc Mathematical Biology and Biophysical Chemistry	University of Warwick	Distinction
2009-2012	BSc Biochemistry	Aberystwyth University	First Class Honours

 

PhD Project

We have available to us a finite number of antibiotics, which we use to treat bacterial infections. Bacteria are developing resistance to these antibiotics. When bacteria develop a resistance to one antibiotic, we use a different antibiotic to treat that infection. MRSA is resistant to methicillins, including penicillin. MRSA is commonly treated with vancomycin. Vancomycin resistance has been recorded since the 1980s, but the mechanism by which bacterial cells achieve it is only partially understood.

Gram-positive bacteria have a layer of peptidoglycan surrounding the cell membrane. The peptidoglycan confers structural stability to the cell. Peptidoglycan precursors are synthesised inside the cell, transported through the membrane and assemble outside the cell into a mesh. Vancomycin binds to precursors when they leave the cell, and prevent them from cross-linking. This results in breakdown of the peptidoglycan layer, and cell death.

A protein in the membrane of resistant cells, VanS, detects the presence of vancomycin in the environment. VanS phosphorylates VanR, which upregulates expression of downstream resistance genes. These genes stop the cell from producing wildtype peptidoglycan precursors, and instead start producing a modified precursor to which vancomycin cannot bind. These precursors integrate into the peptidoglycan layer despite the presence of vancomycin.

VanS is believed to become active when some ligand binds to the extracellular domain of the protein. The identity of that ligand has yet to be elucidated. My project made use of various biophysical techniques - including solution-state NMR and circular dichroism spectroscopy - to investigate changes in the structure of VanS when exposed to potential ligands.

 

Other Commitments

During my PhD I gained experience in supporting the teaching of undergraduate students - mathematics in the Chemistry department, and statistics and biochemistry in the School of Life Sciences. I have found this to be a very rewarding and informative experience, and I hope the students I have worked with would say the same!

I was also fortunate enough to be able to get involved in some of the Chemistry department's various outreach programmes. I feel very strongly that outreach is a crucial component to modern scientific work, and I hope to continue to participate in one form or another as my career progresses.

 

Personal Interests

In my spare time I enjoy running, reading murder mysteries, and cooking. Ask me about my confit chicken wings.

Christine Lockey

MOAC DTC
University of Warwick
Coventry
CV4 7AL

C dot Lockey at warwick dot ac dot uk